The transcriptional co-repressor Runx1t1 is essential for MYCN-driven neuroblastoma tumorigenesis

MYCN oncogene amplification is frequently observed in aggressive childhood neuroblastoma. Using an unbiased large-scale mutagenesis screen in neuroblastoma-prone transgenic mice, we identify a single germline point mutation in the transcriptional corepressor Runx1t1, which abolishes MYCN-driven tumorigenesis. This loss-of-function mutation disrupts a highly conserved zinc finger domain within Runx1t1. Deletion of one Runx1t1 allele in an independent Runx1t1 knockout mouse model is also sufficient to prevent MYCN-driven neuroblastoma development, and reverse ganglia hyperplasia, a known pre-requisite for tumorigenesis. Silencing RUNX1T1 in human neuroblastoma cells decreases colony formation in vitro, and inhibits tumor growth in vivo. Moreover, RUNX1T1 knockdown inhibits the viability of PAX3-FOXO1 fusion-driven rhabdomyosarcoma and MYC-driven small cell lung cancer cells. Despite the role of Runx1t1 in MYCN-driven tumorigenesis neither gene directly regulates the other. We show RUNX1T1 forms part of a transcriptional LSD1-CoREST3-HDAC repressive complex recruited by HAND2 to enhancer regions to regulate chromatin accessibility and cell-fate pathway genes.


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No data were excluded from the analysis All attempts at replication were successful Mice were randomly assigned to doxycycline or control food once their tumours reached 100mm3 Blinding in the doxycycline experiments was not possible as the doxycycline food is coloured red We require information from authors about some types of materials, experimental systems and methods used in many studies.Here, indicate whether each material, system or method listed is relevant to your study.If you are not sure if a list item applies to your research, read the appropriate section before selecting a response.The processed ChIP-sequencing and RNA-sequencing data are available at GEO database under accession code GSE230265 and in our github repository at https://github.com/CCI-bio/RUNX1T1.The ChIPseq dataset of MYCN-amplified Neuroblastoma cell lines data used in this study are available in the GEO database under accession code GSE94824 https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE94824.The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium via the PRIDE partner repository with the dataset identifier PXD050375.The ChIP-sequencing and RNAsequencing data can also be explored/analysed directly via the R2 genomics analysis and visualization platform (https://r2.amc.nl).